Liver Transplantation in Children

Indications for Liver Transplantation for Chronic Liver Failure

The presence of cirrhosis alone should not be considered an indication for LTX, unless signs of hepatic failure are evident. Decompensated liver disease is characterized by clinical and laboratory findings of liver synthetic failure and the occurrence of complications such as malnutrition, ascites, peripheral edema, coagulopathy, gastrointestinal bleeding, and signs of portal hypertension and hepatic encephalopathy. Malnutrition with reduced lean tissue and fat stores and poor linear growth is an important sign of chronic liver disease in children. Spontaneous bruising caused by reduced synthesis of clotting factors and thrombocytopenia due to hypersplenism are both signs of advanced disease in the absence of other causes of hypersplenism. There may also be changes in the systemic and pulmonary circulation, with arteriolar vasodilation, increased blood volume, hyperdynamic circulatory state, and cyanosis due to intrapulmonary shunting. Renal failure is a late but serious event. Laboratory investigations may reveal abnormalities in liver function tests and an increase in ammonia levels, but in particular, there is abnormal liver synthetic function, reflected by such findings as hypoalbuminemia and prolonged prothrombin time (PT). With the marked improvement in patient survival with resultant improvements in quality-of-life measures, the timing of LTX with respect to other medical and surgical options is being constantly reassessed; however, effective alternative therapies should be attempted before referral for LTX. ^,

Timing of Liver Transplantation for Chronic Liver Failure

It may be difficult to plan the best time for LTX for children with chronic liver failure, as many children have compensated liver disease for years. The most useful guide to the timing of LTX is provided by a variety of parameters that include (1) a persistent rise in total bilirubin concentration; (2) prolongation of PT and international normalized ratio (INR); (3) a persistent decrease in serum albumin concentration; and (4) other consequences of portal hypertension such as ascites, variceal bleeding, and fluid retention.

Serial evaluation of nutritional parameters is a useful guide to early hepatic decompensation. Progressive reduction of fat (measured by triceps skinfold or subscapular skinfold) or protein stores (measured by midarm circumference or midarm muscle area) despite intensive nutritional support is a good guide to hepatic decompensation. The development of the pediatric end-stage liver disease (PELD) score has confirmed these observations. The PELD scoring system was developed based on the evaluation of data from the Studies of Pediatric Liver Transplantation (SPLIT), a consortium of 29 U.S. and Canadian centers. In the multivariate analysis, significant factors for predicting outcome were age, bilirubin, INR, growth failure, and albumin. This method has been in use for the last several years and is a useful tool for categorizing patients awaiting transplantation based on their disease severity and their waiting list mortality risk. The following is the formula to determine the PELD score:

PELD score = 10(0.436 [age (<1 year)] − 0.687 × loge[albumin g/dL] + 0.480 × loge[total bilirubin mg/dL] + 1.857 × loge[INR] + 0.667) (Growth failure [<2 standard deviations present]). Scores for patients listed for LTX before the patient’s first birthday who become older than 1 year continue to include the value assigned for age until the patient reaches the age of 24 months + 0.667 (if patient has growth failure of ≤ 2 standard deviations).

In addition to these objective measures, another important consideration in the timing of LTX is psychosocial development. Children with chronic liver disease have both social and motor developmental delay, which increases with time unless reversed after early LTX. ^,

Children with severe hepatic complications, such as chronic hepatic encephalopathy, refractory ascites, intractable pruritus, or recurrent variceal bleeding despite appropriate medical management should be referred for transplantation. In some children, hepatopulmonary syndrome secondary to pulmonary shunting develops and is an important indication for LTX. It is essential that transplantation be performed before the development of severe pulmonary hypertension, as this might preclude successful LTX. ^, The patients with these complications are provided additional priority compared to those patients with a comparable PELD score, recognizing that these complications are not factored into the PELD equation.

For children with chronic liver disease to benefit from transplantation, it is essential that this procedure be considered before the complications of liver disease adversely impair the quality of their life, and before their growth and development are irreversibly retarded ( Chapter 77 ).

Liver Transplantation for Acute Liver Failure

Acute liver failure accounts for approximately 10% of all LTX in children but is associated with high mortality. ^{, ,} It is a heterogeneous condition with many different causes (see Table 78.1 ).

The definition of acute liver failure is the development of hepatic necrosis with hepatic encephalopathy and coagulopathy within 8 weeks of the onset of liver disease, and the absence of preexisting liver disease in any form (the exception is Wilson disease). This definition is not useful in children, and especially the younger age group, because encephalopathy is difficult to detect or may not be a feature in infants. In addition, acute liver failure may be the first manifestation of an unrecognized metabolic liver disease (e.g., Wilson disease or tyrosinemia type I). In addition, most hepatic failure in neonates is secondary to an inborn error or an intrauterine insult, which would be considered a preexisting liver disease.

The etiology of acute liver failure varies depending on the age of the child (see Table 78.1 ). In neonates, an inborn error of metabolism or severe infection is likely, whereas viral hepatitis, autoimmune liver disease, drug-induced liver failure, and Wilson disease are common causes in older children. ^{, ,}

The prognosis of acute liver failure is worse in the younger ages. Severe coagulopathy, severe metabolic acidosis, cardiovascular instability, and renal failure are signs of a poor prognosis. Age less than 10 years, INR of more than 4, and cryptogenic origin of the disease carry a mortality of more than 80% without LTX. More recently, the Pediatric Liver Failure Study Group reported on the usefulness of the assay of inflammatory mediators based on application of dynamic Bayesian network (DBN) analysis of these mediators. The investigators looked at these mediators in a small patient sample and concluded that there are differences between survivors and nonsurvivors. In general, in addition to all the poor prognostic signs, progression of encephalopathy to stage III in these patients is an indication for expedited LTX. One-year patient survival in this setting is inferior to that of LTX for chronic liver disease, being 75% to 80%. ^, The key to management of these patients, either supportive or as a bridge to LTX, is prevention of complications of acute liver failure. Treatment of coagulopathy, management of fluid and electrolyte balance, support of renal function, and prevention of infection, cerebral edema, and intracranial hypertension are the prime goals in management of these patients. ^,

The use of N -acetylcysteine (NAC) in pediatric patients with non-acetaminophen acute liver failure has been studied by the Pediatric Acute Liver Failure Group. The study was designed as a double-blind, placebo-controlled study to look at 1-year survival, LTX-free survival, post-LTX survival rate, organ system failure, and level of hepatic encephalopathy score. The study concluded that the overall 1-year survival was not significantly different between the two groups. The 1-year LTX-free survival was significantly lower in the NAC group (35% vs. 53%), and there was no significant difference in intensive care unit (ICU) length of stay and hepatic encephalopathy score.

Liver Transplantation for Hepatic Malignancies

Pediatric primary hepatic malignancies have an incidence of 1:1,000,000 and account for 0.5% to 2% of solid tumors in children. ^, The most common tumor is hepatoblastoma (HB), accounting for approximately 28% of all pediatric liver malignancies. Hepatocellular carcinoma (HCC; 18.9%) and infantile hemangioendotheliomas (16.5%) are other common malignant tumors of the liver in children. ^, Total excision with or without adjuvant chemotherapy is the treatment of choice for these tumors. However, in patients with unresectable and chemoresistant tumors, complete surgical excision in the form of total hepatectomy and LTX is a viable option. The Society of International Paediatric Oncology (SIOP) developed a pretreatment and presurgery system to assess the tumor extent and prognosis called PRETreatment EXTension of disease (PRETEXT), which has become the basis for treatment planning in patients with HB. Patients with PRETEXT I, II, and some III categories are generally amenable to conventional therapy with chemotherapy and resection. Those patients in the PRETEXT IV category require LTX. ^, The role of LTX in the treatment of hepatic malignancies in children is still to be evaluated. Post-LTX survival depends on the stage of the tumor and nature of the malignancy.

Hepatic Function

Listing for LTX is based on evidence of deterioration in hepatic function as indicated by serum albumin concentration (<3.5 g/dL), coagulation time (INR more than 1.4), and cholestasis as evidenced by a rise in bilirubin concentration (more than 8 mg/dL). In children with chronic liver failure, the presence of portal hypertension should be determined by estimating the size of the spleen and portal vein (PV) by ultrasonography and by surrogate markers such as the presence of a low white blood cell count and platelet count as a result of hypersplenism, and/or the identification of esophageal and/or gastric varices by gastrointestinal endoscopy.

Renal Function

Children with acute or chronic liver failure have abnormalities of renal function in the form of primary renal disease or hepatorenal syndrome. Assessment of renal function is important to provide a baseline due to the nephrotoxic effect of immunosuppressive drugs following transplantation, and to evaluate the necessity for perioperative renal support, placement on renal-sparing immunosuppressive protocols, or in case of chronic renal insufficiency, listing for combined liver and kidney transplantation (LKTx). In addition, children with fulminant liver failure may develop oliguria or anuria as a result of hepatorenal syndrome and may need renal replacement therapy (dialysis, hemofiltration therapy).

Hematology and Coagulation Profile

Baseline information on full blood count, platelets, and coagulation is obtained. Determination of blood group is essential for organ donor matching.

Serology

Previous evidence of varicella, measles, or infection with hepatitis A, B, or C viruses, cytomegalovirus (CMV), or Epstein-Barr virus (EBV) is important information for postoperative management and placement on prophylactic protocols.

Radiology

Successful LTX requires thorough preoperative knowledge of hepatic vascular anatomy and patency and liver size. This is critical for surgical planning of revascularization of the new liver. Doppler sonography is performed routinely as surveillance preoperatively and provides information regarding the size and patency of the PV, hepatic veins, IVC, and hepatic artery. Children with biliary atresia have an increased incidence of abnormal vasculature including the hypovascular syndrome, which consists of an absent IVC, preduodenal or absent PV, and hepatic outflow abnormalities. Polysplenia in association with situs inversus and dextrocardia are other potential findings in these patients. Because these abnormalities may increase the technical risk associated with LTX, it is important to diagnose them before the procedure. However, none of these is a contraindication to LTX.

Cardiac and Respiratory Assessment

LTX is associated with significant hemodynamic changes during the operative and anhepatic phases, and information on both cardiac and respiratory function is needed. Preoperatively, electrocardiography, echocardiography, and oxygen saturation provide most of the necessary information for management of these hemodynamic changes. Children with biliary atresia have an increased incidence of congenital cardiac disease, particularly atrial and ventricular septal defects, whereas peripheral pulmonary stenosis and other vascular anomalies are known features of Alagille syndrome (see Chapter 70 ). Cardiomyopathy may develop secondary to tyrosinemia type I and organic acidemia, and children with malignant tumors who have received chemotherapy prior to transplantation need particular cardiac assessment. Cardiac catheterization is required in some cases to determine whether cardiac function is adequate to sustain the hemodynamic effect of LTX, or whether cardiac surgery or other interventions may be required before transplantation. In some cases with large atrial septal defects, a paradoxical cerebral vascular accident may occur if a venous embolism should traverse the defect and embolize to the brain. If the cardiac defect is uncorrectable, LTX occasionally may be contraindicated.

The development of intrapulmonary shunts (hepatopulmonary syndrome) is detected by measuring serial arterial blood gases while breathing room air and 100% oxygen, or by Tc-99m-macroaggregated albumin scan and contrast echocardiography. ^,